Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain.

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy with respect to existing therapies and reduce their unwanted effects. Current preclinical evidence supports the modulatory role of sigma-1 receptors (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pains of different etiologies. σ1R is highly expressed in different pain areas of the CNS and the periphery (particularly dorsal root ganglia), and interacts and modulates the functionality of different receptors and ion channels . The antagonism of σ1R leads to decreased amplification of pain signaling within the spinal cord (central sensitization), but recent data also support a role at the periphery. σ1R antagonists have consistently demonstrated efficacy in neuropathic pain , but also in other types of pain including inflammatory, orofacial, visceral, and post-operative pain. Apart from acting alone, when combined with opioids, σ1R antagonists enhance opioid analgesia but not opioid-induced unwanted effects. Interestingly, unlike opioids, σ1R antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitive effects in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. Accordingly, σ1R antagonists are not strictly analgesics; they are antiallodynic and antihyperalgesic drugs acting when the system is sensitized following prolonged noxious stimulation or persistent abnormal afferent input (e.g., secondary to nerve injury). These are distinctive features allowing σ1R antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain .

Sigma-1 receptor and inflammatory pain.

INTRODUCTION: The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain. DISCUSSION: Recent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary. CONCLUSION: Central and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.

S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice.

The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (σ1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to σ1R knockout mice, thus suggesting the involvement of σ1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain.

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ-1 Subunit of Voltage-Gated Calcium Channel and the µ-Opioid Receptor.

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the µ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Cavα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.

"Bedside-to-Bench" Behavioral Outcomes in Animal Models of Pain: Beyond the Evaluation of Reflexes.

Despite the myriad promising new targets and candidate analgesics recently identified in preclinical pain studies, little translation to novel pain medications has been generated. The pain phenotype in humans involves complex behavioral alterations, including changes in daily living activities and psychological disturbances. These behavioral changes are not reflected by the outcome measures traditionally used in rodents for preclinical pain testing, which are based on reflexes evoked by sensory stimuli of different types (mechanical, thermal or chemical). These measures do not evaluate the impact of the pain experience on the global behavior or disability of the animals, and therefore only consider a limited aspect of the pain phenotype. The development of relevant new outcomes indicative of pain to increase the validity of animal models of pain has been increasingly pursued over the past few years. The aim has been to translate "bedside-to-bench" outcomes from the human pain phenotype to rodents, in order to complement traditional pain outcomes by providing a closer and more realistic measure of clinical pain in rodents. This review summarizes and discusses the most important nonstandard outcomes for pain assessment in preclinical studies. The advantages and drawbacks of these techniques are considered, and their potential impact on the validation of potential analgesics is evaluated.

Resilience to Pain-Related Depression in σ1 Receptor Knockout Mice Is Associated with the Reversal of Pain-Induced Brain Changes in Affect-Related Genes.

Mice lacking the σ1 receptor chaperone (σ1R-/-) are resilient to depressive-like behaviors secondary to neuropathic pain. Examining the resilience's brain mechanisms could help develop conceptually novel therapeutic strategies. We explored the diminished motivation for a natural reinforcer (white chocolate) in the partial sciatic nerve ligation (PSNL) model in wild-type (WT) and σ1R-/- mice. In the same mice, we performed a comprehensive reverse transcription quantitative PCR (qPCR) analysis across ten brain regions of seven genes implicated in pain regulation and associated affective disorders, such as anxiety and depression. PSNL induced anhedonic-like behavior in WT but not in σ1R-/- mice. In WT mice, PSNL up-regulated dopamine transporter (DAT) and its rate-limiting enzyme, tyrosine hydroxylase (Th), in the ventral tegmental area (VTA) and periaqueductal gray (PAG) as well as the serotonin transporters (SERT) and its rate-limiting enzyme tryptophan hydroxylase 2 (Tph2) in VTA. In addition, µ-opioid receptor (MOR) and σ1R were up-regulated in PAG, and MOR was also elevated in the somatosensory cortex (SS) but down-regulated in the striatum (STR). Finally, increased BDNF was found in the medial prefrontal cortex (mPFC) and hypothalamus (HPT). Sham surgery also produced PSNL-like expression changes in VTA, HPT, and STR. Genetic deletion of the σ1R in mice submitted to PSNL or sham surgery prevented changes in the expression of most of these genes. σ1R is critically involved in the supraspinal gene expression changes produced by PSNL and sham surgery. The changes in gene expression observed in WT mice may be related to pain-related depression, and the absence of these changes observed in σ1R-/- mice may be related to resilience.

Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor.

Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk). We characterized over time a reward-seeking task based on diminished motivation for natural reinforcers (anhedonic-like behavior). To differentiate the appetitive ("wanting") and consummatory ("liking") aspects of motivational behavior, we quantified the latency and number of approaches to eat white chocolate, as well as the eating duration and amount consumed. We explored a putative chronic pain-induced dysregulation of monoamine function by measuring monoamine levels in the nucleus accumbens (NAc), a well-known brain reward area. Finally, we investigated the role of sigma-1 receptor (σ1R) modulation, a nonopioid target, in these multiple dimensions by genetic deletion and pharmacological dose-response studies. After 6 weeks, PSNL increased the approach latency and reduced the consumption of white chocolate in 20-25% of the mice, while around 50-60% had one or the other parameter affected independently. After 10 weeks, sham-operated mice also displayed anhedonic-like behavior. PSNL was associated with reduced extracellular baseline dopamine and increased norepinephrine in the NAc and with a suppression of increased dopamine and serotonin efflux in response to the rewarding stimulus. Genetic and pharmacological blockade of σ1R relieved these multiple alterations in nerve-injured mice. We comprehensively describe sensory, functional, and depression-like impairment of key components of motivated behavior associated with nerve injury. We provide a neurochemical substrate for the depressed mesocorticolimbic reward processing in chronic pain, with a potentially increased translational value. Our results also highlight σ1R for the therapeutic intervention of neuropathic pain.

Administration of the sigma-1 receptor agonist PRE-084 at emerging adulthood, but not at early adolescence, attenuated ethanol-induced conditioned taste aversion in female rats.

Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels.

The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido[4,3-d]pyrimidin-4(3H)-one 16RR, which showed high selectivity for Cavα2δ-1 versus Cavα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.

Propionamide Derivatives as Dual µ-Opioid Receptor Agonists and σ1 Receptor Antagonists for the Treatment of Pain.

A new series of propionamide derivatives was developed as dual µ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.

A bibliometric analysis of research in psychopharmacology by psychology departments (1987-2007).

From the very outset of scientific Psychology, psychologists have shown interest for drugs and their effects on behavior. This has given rise to numerous contributions, mostly in the form of Psychopharmacology publications. The aim of this study was to quantitatively evaluate these contributions and compare them with other academic disciplines related to Psychopharmacology. Using the PubMed database, we retrieved information about articles from 15 journals included in the Pharmacology and Pharmacy category of the Journal Citation Reports database for a 21-year period (1987 to 2007). There were 37540 articles which about 52% were represented by 3 journals. About 70% of psychology publications were represented by 2 of these journals. Psychology departments accounted for the 11% of the published papers, which places Psychology third behind Psychiatry and Pharmacology, which contributed to 22.69 and 13% respectively. Psychology contributed to the greatest number of studies in 3 journals, second in 3 and third in 8. This report represents the first effort to explore the contribution of academic Psychology to the multidisciplinary science of psychopharmacology. Although leaders of production of psychopharmacology research were from Psychiatry and Pharmacology, Psychology departments are an important source of studies and thus of knowledge in the field of Psychopharmacology.

Sigma-1 antagonism inhibits binge ethanol drinking at adolescence.

BACKGROUND: Ethanol use during adolescence is a significant health problem, yet the pharmacological treatments to reduce adolescent binge drinking are scarce. The present study assessed, in male and female adolescent Wistar rats, if the sigma-1 receptor (S1-R) antagonists S1RA or BD-1063 disrupted ethanol drinking. METHODS: Three times a week, for two weeks, the rats received the S1-R antagonists. Thirty min later they were exposed, for 2 h, to a bottle of 8% or 10 % v/v ethanol. A 24 h, two-bottle, ethanol intake test was conducted after termination of these procedures. A subset of these rats was tested for recognition memory via the novel object recognition test. RESULTS: The rats given 64 mg/kg S1RA drank, in each binge session, significantly less than vehicle counterparts. Male rats given 4 or 16 mg/kg S1RA drank significantly less than those given 0 mg/kg in session 3 or in session 1 and 2, respectively; whereas female rats given 4 or 16 mg/kg drank significantly less than females given 0 mg/kg in session 2-5 or in sessions 2-6, respectively. Administration of 32 mg/kg, but not of 2 or 8 mg/kg, BD-1063 suppressed, across sessions, ethanol drinking. S1-R antagonism reduced absolute ethanol drinking at the two-bottle choice post-test. Recognition memory was not affected by the ethanol exposure. CONCLUSIONS: The results indicate that S1-R antagonists may be promising targets to prevent increases in ethanol intake at adolescence. The persistent effect of S1-R antagonism in free-choice drinking suggests that modulation of the S1-R is altering plastic effects associated with ethanol exposure.

Trends in Sigma-1 Receptor Research: A 25-Year Bibliometric Analysis.

Purpose: There are previous reviews focused on Sigma-1 receptor but no bibliometric studies examining this field as a whole. This article aims to present a global view of Sigma-1 receptor research and its intellectual structure. Methods: We used bibliometric indicators of a basic nature as well as techniques for the visualization and analysis of networks of scientific information extracted from Scopus database. Results: In total, 1,102 articles from 1992 to 2017 were identified. The growth in the production of articles is not constant over time, with periods of stagnation of approximately 5 years. Only 247 authors have five or more publications. The authors appear grouped in relatively independent clusters, thus suggesting a low level of collaborations between those dedicated to the Sigma-1 receptor. The United States was the country with the highest production followed by Japan and Germany. Spain, Japan, and Italy showed the highest per million inhabitants ratio. The highest citation/article ratio was reached in France, United States, and Canada. The leading institutions were the University of Münster, the National Institutes of Health, ESTEVE, and INSERM. The top authors in number of publications were Wünsch-B, Schepmann-D, and Maurice-T. Hayashi-T, Su-TP and Bowen-WD showed the highest citations per article. The article by Hayashi-T and Su-TP in Cell (2007) describing the Sigma-1 receptor as a chaperone protein is the top cited reference. Cluster labeling from author co-citation analysis shows that research has been focused on specific diseases such as addiction, neuroprotection and neurodegenerative diseases, psychiatric disorders, and pain. High-frequency terms in author keywords suggest that the research efforts in some areas such as neuroimaging, cocaine addiction or psychiatric disorders have declined over time, while others such as neurodegenerative diseases or pain are currently most popular. Perspective: A greater involvement of the scientific community, with an increase in the scientific production related to Sigma-1, is desirable. Additional boost needed to improve research performance is likely to come from combining data from different laboratories to overcome the limitations of individual approaches. The resulting maps are a useful and attractive tool for the Sigma-1 receptor research community, as they reveal the main lines of exploration at a glance.

Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctcsusp) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctcsusp exerted synergistic mechanical antiallodynic (experimental ED50 = 2.0 ±â€¯0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ±â€¯0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ±â€¯0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ±â€¯0.8 mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctcsusp. Overall, rat efficacy and safety data revealed that ctcsusp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctcsusp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctcsusp supports the further investigation of CTC in the clinical management of moderate-to-severe acute pain as an alternative to strong opioids.

Pharmacological sensitivity of reflexive and nonreflexive outcomes as a correlate of the sensory and affective responses to visceral pain in mice.

Pain encompasses both sensory and affective dimensions which can be differentially modulated by drugs. Here, we compare the pharmacological sensitivity of the sensory and affective responses using acetic acid-induced abdominal writhings (sensory-reflexive outcome) and acetic acid-induced depression of reward seeking behaviour (RSB, affective-nonreflexive outcome) to a highly palatable food in mice. We found that the expression of RSB critically depends on factors such as sex and previous knowledge and type of the food stimulus. Intraperitoneal administration of acetic acid (iAA) produced a long-lasting (beyond the resolution of writhing behaviour) and concentration-dependent decrease on both appetitive-approach and consummatory dimensions of RSB. Ibuprofen and diclofenac were much more potent in reversing AA-induced changes in RSB: latency to eat (ED50 = 2 and 0.005 mg/kg, intraperinoneally, respectively) and amount consumed (ED50 = 11 and 0.1 mg/kg) than in AA-induced writhing (ED50 = 123 and 60 mg/kg). Morphine and duloxetine inhibited the writhing response (ED50 = 0.8 and 6 mg/kg, respectively) but not the AA-induced changes in RSB. Caffeine was ineffective in both AA-induced writhing and RSB changes. Overall, this study characterized a preclinical mouse model of hedonic deficits induced by pain that can be used to assess affective responses as well as complementary classic reflexive approaches in the evaluation of candidate analgesics.

Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia.

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs. However, inflammation-induced tactile allodynia lasted longer than grip strength alterations, and therefore did not drive the functional deficits. Oral administration of the opioid drugs oxycodone (1-8 mg/kg) and tramadol (10-80 mg/kg) induced a better recovery of grip strength than acetaminophen (40-320 mg/kg) or the nonsteroidal antiinflammatory drugs ibuprofen (10-80 mg/kg) or celecoxib (40-160 mg/kg); these results are consistent with their analgesic efficacy in humans. Functional impairment was generally a more sensitive indicator of drug-induced analgesia than tactile allodynia, as drug doses that attenuated grip strength deficits showed little or no effect on von Frey thresholds. Finally, ruthenium red (a nonselective TRP antagonist) or the in vivo ablation of TRPV1-expressing neurons with resiniferatoxin abolished tactile allodynia without altering grip strength deficits, indicating that the neurobiology of tactile allodynia and grip strength deficits differ. In conclusion, grip strength deficits are due to a distinct type of pain that reflects an important aspect of the human pain experience, and therefore merits further exploration in preclinical studies to improve the translation of new analgesics from bench to bedside.

The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.

E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.

Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice.

RATIONALE: Formalin-induced pain is reduced in sigma-1 (sigma1) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for sigma1 receptors, may modulate formalin-induced pain. RESULTS: Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03-1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25-8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4-128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (-)sulpiride (200 mg/kg), which have no affinity for sigma1 receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol>metabolite II>metabolite I>>metabolite III= (-)sulpiride=inactive] correlated with their affinity for sigma1 receptors, but not with their affinity for sigma2 or dopamine D2 receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test. CONCLUSION: These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with sigma1 receptors.

Formalin-induced pain is reduced in sigma(1) receptor knockout mice.

The role of sigma1 receptors in non-acute pain has not been explored. In this study we show that both phases of formalin-induced pain were reduced by approximately 55% in sigma1 receptor knockout mice in comparison to wild-type animals. These results suggest that the tonic pain induced by formalin is altered in mice lacking sigma1 receptors, and highlight the potential usefulness of further studies of the role of sigma1 receptors in models of non-acute pain.